Designer Hormones

Researchers at the University are on the leading edge of molecular design, using sophisticated computer techniques to generate models of molecules. Those molecules then can be synthesized in the laboratory and may ultimately lead to new treatments for genetic diseases.

John T. Koh, associate professor of chemistry and biochemistry, directs a team that is working to create hormone analogs that will work more efficiently with mutated forms of receptors that otherwise cause genetic disease.

The American Chemical Society cited the team's work as among the leading biochemistry research developments of 2002 in the Dec. 16 issue of its publication, Chemical & Engineering News.

"We have a tremendous amount of information about the biology and chemical structure of hormones and their receptors," Koh says. "Because of that, we can use computer models to see how they normally work and how they don't work when they contain mutations. Using these models, we can design new hormones that restore normal function to these otherwise defective receptors."

The group is focusing on vitamin D, which, despite the name, is a hormone.

Koh says a small number of persons worldwide suffer from a debilitating and ultimately fatal disease called Vitamin D Resistant Rickets (VDRR), in which a mutated gene causes a dysfunctional vitamin D receptor.

A disease caused by a vitamin D deficiency, rickets leads to a grave thinning of the bones. One relatively benign form can be cured by proper diet and exposure to sunlight or by taking vitamin D directly. However, VDRR, the form of the disease that is the result of a genetic defect to the receptor, cannot be treated by these methods. VDRR can be so severe that, often, patients who suffer from it do not reach adulthood.

Koh likens the root cause of the disease to a molecular lock and key that regulates gene expression. Vitamin D is the key, but in VDRR patients, it no longer fits into their lock because the locks are defective.

"If we can understand the structure, we can engineer and create a hormone analog that will match the defective receptor," Koh says. In other words, the researchers can design a new key that will fit the defective lock. This technique differs from gene therapy, in which the gene that forms the lock would be modified to accept the key.

In laboratory efforts to design a working key, Koh and graduate student Steven Swann have seen what Koh calls "fantastic results."

"We have developed compounds that show really dramatic activity at the cellular level," he says. He cautions, however, that the laboratory findings have not yet been applied to humans.

The distinctly multidisciplinary Koh group, which includes both graduate and undergraduate researchers, is working in collaboration with a biological research team because there are two forms of vitamin D receptors, one nuclear and one a membrane. That team is headed by Mary C. Farach-Carson, professor of biological sciences.

"We are collaborating with her group to evaluate compounds in the membrane receptor," Koh says. "If a compound can turn on the nuclear vitamin D receptor but creates problems with the membrane receptor, it would be of no benefit to the patient. We are trying to create selective solutions that can solve problems, while at the same time not creating adverse side effects."

In the long run, he says, the research is exciting because many genetic diseases are relatively rare, and there is no economy of scale to entice large pharmaceutical companies to develop drugs to provide a cure.

"It costs hundreds of millions of dollars to develop drugs, and you can't do that for a small population," Koh says. "Through this method, we can use computers to help do the work more efficiently. If effective, it may enable the development of drugs for small patient populations."

Such science is made possible by exponential leaps in knowledge and technology over the last two decades, he says, adding, "We can understand the biology at the molecular level. It is to the point that we can see the atomic level structure of many biological systems, and that is pretty remarkable."

By zeroing in at the atomic level and gaining an understanding of how a genetic structure is defective, Koh says scientists can design molecules to compensate for certain molecular defects.

"With the computer, you can make a model and predict how the compound will be used in the receptor, how you can modify to fit the lock," he says. "That is called 'virtual screening,' which is a hot term at the moment. You can make and evaluate molecules on the computer, select the best candidates to actually create in the laboratory and then measure their biological activities."

In addition to working with Farach-Carson and graduate student Joel Bergh from her group, Koh says his own research team was developed as a multidisciplinary unit so that it has expertise in computer-aided molecular design, chemical synthesis and molecular and cell biology.

Koh says Swann has made a huge contribution to the research, conducting work in computer design and chemical synthesis. He also performed much of the molecular and cell biology used to evaluate the compounds. Swann was assisted by Cory Ocasio, an undergraduate researcher who now is in graduate school studying chemical biology at the University of California at San Francisco.

--Neil Thomas, AS'76